Therapeutically effective treatment of neurodegenerative diseases continues to be an area of unmet medical need. In the face of an aging population throughout the industrialized nations, this need will continue to grow for the foreseeable future. In 2010, the CDC estimated that by the year 2030, the U.S. population over 65 will double to about 71 million.
Opportunities for small molecule therapeutic intervention are promising. It is now accepted that the adult vertebrate brain fosters the birth and functional incorporation of newly formed neurons (Goldman and Nottebohm, 1984; Paton and Nottebohm, 1984; Burd and Nottebohm, 1985). It is also now accepted that within all mammalian species, including humans (Eriksson et al., 1998), there are two major reservoirs of neuronal stem cells, one located in the subgranular zone (SGZ) of the hippocampal dentate gyrus and another in the subventricular zone (SVZ) (Gross, 2000). Neural stem cells in the SVZ facilitate formation of new neurons that migrate rostrally to populate the olfactory bulb, while neural stem cells in the SGZ produce neurons that integrate locally in the granular layer of the dentate gyrus, a region of the hippocampus that exhibits lifelong structural and functional plasticity.
Bombrun, et. al., J. Med. Chem., 2003, Vol. 46, No. 21, 4365-68, discloses small molecules which, in isolated mitochondria prevent cytochrome c release induced by the BH3 only protein BID. This effect was suggested to be related to the molecule's ability to prevent permeabilization of the outer mitochondrial membrane. This effect was confirmed by Peixoto in 2009 demonstrating that such compounds do indeed inhibit mitochondrial permeabilization by preventing the formation of mitochondrial apoptosis channels (MAC) (Peixoto, et al., Biochem J, 2009, 423, 381-387). Pieper, et. al., Cell 142, 39-51, Jul. 9, 2010, provides evidence that small molecule P7C3 exerts proneurogenic activity by preventing apoptosis of “newborn” hippocampal neurons. And Sachdeva and Burns, CNS Neuroscience & Therapeutics, Vol. 17 (2010) 199-205, reviewed Dimebolin, a small molecule non-selective anti-histamine, which in some studies appears to have had beneficial effects on several symptoms of Alzheimer's type dementia.
Apoptosis plays a substantial role in cell death that occurs in conjunction with various disease and injury conditions. For example, apoptosis leads to neuronal loss associated with neurodegenerative disorders, including Alzheimer's disease (Barinaga, Science 281:1303-1304), Huntington's disease, spinal-muscular atrophy, stroke (reviewed in Rubin, British Med. Bulle., 53(3):617-631, 1997; and Barinaga, Science 281:1302-1303), and transient ischemic neuronal injury, as in spinal cord injury. Accordingly, it would be of great benefit to prevent undesired apoptosis in these various diseases and injury situations.
The mitochondrial apoptosis-induced channel, MAC, is induced early in apoptosis (Pavlov, E. V., Priault, M., Pietkiewicz, D., Cheng, E. H., Antonsson, B., Manon, S., Korsmeyer, S. J., Mannella, C. A. and Kinnally, K. W. (2001), J Cell Biol 155, 725-31). The high conductance (2-6 nS) suggests MAC has a pore that is >4 nm in diameter. Evidence is mounting that MAC provides the pathway through the outer membrane for release of the 3.3 nm diameter cytochrome c. Not only does cytochrome c reduce the conductance of MAC in a manner consistent with its partitioning into the pore of MAC (Guo, L., Pietkiewicz, D., Pavlov, E. V., Grigoriev, S. M., Kasianowicz, J. J., Dejean, L. M., Korsmeyer, S. J., Antonsson, B. and Kinnally, K. W. (2004), Am J Physiol Cell Physiol 286, C1109-17), but proteoliposomes expressing MAC activity fail to retain cytochrome c. MAC activity is present in multiple different cell types (CSM14.1, and various clones of FL5.12 and HeLa cells) during cytochrome c release. More recently, Peixoto, P. M., et. al., Biochem. J. (2009), 423, 381-387 discloses MAC inhibitors that suppress mitochondrial apoptosis. It is our belief that inhibiting or preventing the formation or the opening of MAC may, therefore, retard or prevent neurodegeneration.